1. Field of the Invention
This invention is related to specific targeting of biologically-active compounds to specific cells, tissues and organs in vivo. The invention specifically provides conjugates of biologically-active compounds and methods of effecting the uptake and accumulation of biologically active compounds into organs, tissues and cells, particularly at physiologically protected sites, at pharmacokinetically useful levels. The conjugates of this invention permit drug concentrations to be achieved, especially at physiologically protected sites, at levels at which such compounds are therapeutically effective after administration of systemic levels much lower than currently attainable otherwise. This technology is appropriate for rapid and efficient introduction of a variety of biologically active compounds, particularly antibacterial, antibiotic, antiviral, antimycotic, antiproliferative and antineoplastic drugs and agents, and neurotropic, psychotropic and anticonvulsant drugs and agents, to biologically protected sites, for example across the blood-brain barrier.
2. Background of the Invention
A major goal in the pharmacological arts has been the development of methods and compositions to facilitate the specific delivery of therapeutic and other agents to the appropriate cells and tissues that would benefit from such treatment, and the avoidance of the general physiological effects of the inappropriate delivery of such agents to other cells or tissues of the body. One common example of the need for such specificity is in the field of neurologic agent therapy for the treatment of diseases of the central nervous system, particularly the brain, which is protected by a layer of endothelial cells and other structures collectively known as the blood-brain barrier. In the pharmacological and neurologic arts, it is well-recognized that the inability to deliver effective amounts of neurotropic, psychotropic and anticonvulsant drugs and agents across the blood-brain barrier severely limits the therapeutic efficacy of such pharmaceutical compounds and can prevent treatment of neurologic disease. In addition, the use of even effective neurologic agents is further limited by systemic toxicity resulting from the high systemic concentrations that must be administered to achieve a therapeutic concentration of such agents in the brain, central nervous system and other neurological structures. Similar considerations apply in other organs and tissues in mammals that are protected by such blood-related barriers, such as the testes.
Another example of the need for such specificity is for introducing or administering antimicrobial, antiviral and antiproliferative and antineoplastic compounds, drugs or agents, into physiologically-protected reservoirs in an animal such as the brain, central nervous system, eyes and testes. Avoiding general systemic side-effects is particularly important in administering antimicrobial, antiviral and antiproliferative and antineoplastic compounds, drugs or agents targeted to such physiologically-protected sites, since achieving clinically useful concentrations of said compounds at these sites has frequently required administration of high systemic dosages which are associated with greater-than-acceptable levels of systemic toxicity.
It is desirable to increase the efficiency and specificity of administration of a therapeutic agent to the cells of the relevant tissues protected by physiological barriers (e.g., the blood-brain barrier) in a variety of pathological states. Psychotropic, neurological and neurotropic agents and antimicrobial, antiviral and antiproliferative and antineoplastic compounds typically have systemic effects, including renal and hepatotoxicity, hematopoietic suppression, teratogenic capacity, partitioning into breast milk and other pleiotropic cytotoxic effects that damage or otherwise deleteriously impact on uninvolved cells and tissues. Thus, an efficient delivery system which would enable the delivery of such drugs specifically to cells and tissues in such physiologically protected sites would increase the efficacy of treatment and reduce the associated “side effects” of such drug treatments, and also serve to reduce morbidity and mortality associated with clinical administration of such drugs. In addition, specific targeting of specific organs, tissues or cells wherein a biologically active compound preferentially accumulates in a specific organ, tissue or cell and does not generally or systemically accumulate in organs, tissues or cells in a body is desirable.
An additional challenge in designing an appropriate drug delivery scheme is to include within the drug conjugate a functionality that could either accelerate or reduce the rate at which the drug is released upon arrival at the desired site. Such a functionality would be especially valuable if it allowed differential rates of drug release, or specific release only at the appropriate drug target site comprising a specific organ, tissue or cell in a body.
Drug Targeting
Numerous methods for enhancing the biological activity and the specificity of drug action have been proposed or attempted (see, for example, Kreeger, 1996, The Scientist, Sep. 16, 1996, p. 6). To date, however, efficient or specific drug delivery remains to be predictably achieved.
U.S. Pat. No. 5,017,566, issued May 21, 1991 to Bodor discloses β- and γ-cyclodextrin derivatives comprising inclusion complexes of lipoidal forms of dihydropyridine redox targeting moieties.
U.S. Pat. No. 5,023,252, issued Jun. 11, 1991 to Hseih disclose the use of pharmaceutical compositions comprising a neurologically active drug and a compound for facilitating transport of said drug across the blood-brain barrier including a macrocyclic ester, diester, amide, diamide, amidine, diamidine, thioester, dithioester, thioamide, ketone or lactone.
U.S. Pat. No. 5,024,998, issued Jun. 18, 1991 to Bodor discloses parenteral solutions of aqueous-insoluble drugs with β- and γ-cyclodextrin derivatives.
U.S. Pat. No. 5,039,794, issued Aug. 13, 1991 to Wier et al. disclose the use of a metastatic tumor-derived egress factor for facilitating the transport of compounds across the blood-brain barrier.
U.S. Pat. No. 5,112,863, issued May 12, 1992 to Hashimoto et al. disclose the use of N-acyl amino acid derivatives as antipsychotic drugs for delivery across the blood-brain barrier.
U.S. Pat. No. 5,124,146, issued Jun. 23, 1992 to Neuwelt disclose a method for delivery of therapeutic agents across the blood-brain barrier at sites of increase permeability associated with brain lesions.
U.S. Pat. No. 5,149,794, issued Sep. 22, 1992 to Yatvin et al. discloses lipid conjugates with antineoplastic and antiviral drugs.
U.S. Pat. No. 5,153,179, issued Oct. 6, 1992 to Eibl discloses acylated glycerol and derivatives for use in a medicament for improved penetration of cell membranes.
U.S. Pat. No. 5,177,064, issued Jan. 5, 1993 to Bodor discloses the use of lipoidal phosphonate derivatives of nucleoside antiviral agents for delivery across the blood-brain barrier.
U.S. Pat. No. 5,223,263, issued Jun. 29, 1993 to Hostetler et al. discloses conjugates between antiviral nucleoside analogues and polar lipids, including phospholipids and ceramide.
U.S. Pat. No. 5,254,342, issued Oct. 19, 1993 to Shen et al. disclose receptor-mediated transcytosis of the blood-brain barrier using the transferrin receptor in combination with pharmaceutical compounds that enhance or accelerate this process.
U.S. Pat. No. 5,256,641, issued Oct. 26, 1993 to Yatvin et al. discloses lipid conjugates with antigenic peptides.
U.S. Pat. No. 5,258,402, issued Nov. 2, 1993 to Maryanoff discloses treatment of epilepsy with imidate derivatives of anticonvulsive sulfamate.
U.S. Pat. No. 5,270,312, issued Dec. 14, 1993 to Glase et al. discloses substituted piperazines as central nervous system agents.
U.S. Pat. No. 5,284,876, issued Feb. 8, 1994 to Shashoua et al., disclose fatty acid conjugates of dopanergic drugs for tardive dyskinesia.
U.S. Pat. No. 5,389,623, issued Feb. 14, 1995 to Bodor discloses the use of lipoidal dihydropyridine derivatives of anti-inflammatory steroids or steroid sex hormones for delivery across the blood-brain barrier.
U.S. Pat. No. 5,405,834, issued Apr. 11, 1995 to Bundgaard et al. discloses prodrug derivatives of thyrotropin releasing hormone.
U.S. Pat. No. 5,413,996, issued May 9, 1995 to Bodor disclose acyloxyalkyl phosphonate conjugates of neurologically-active drugs for anionic sequestration of such drugs in brain tissue.
U.S. Pat. No. 5,434,137, issued Jul. 18, 1995 to Black disclose methods for the selective opening of abnormal brain tissue capillaries using bradykinin infused into the carotid artery.
U.S. Pat. No. 5,442,043, issued Aug. 15, 1995 to Fukuta et al. disclose a peptide conjugate between a peptide having a biological activity and incapable of crossing the blood-brain barrier and a peptide which exhibits no biological activity and is capable of passing the blood-brain barrier by receptor-mediated endocytosis.
U.S. Pat. No. 5,466,683, issued Nov. 14, 1995 to Sterling et al. disclose water soluble analogues of the anticonvulsant Tegretol® (carbamazepine) for the treatment of epilepsy.
U.S. Pat. No. 5,484,809, issued Jan. 16, 1996 to Hostetler et al. discloses taxol and taxol derivatives conjugated to phospholipids.
U.S. Pat. No. 5,484,911, issued Jan. 16, 1996 to Hong et al. disclose nucleoside analogues conjugates to lipid moieties.
U.S. Pat. No. 5,512,671, issued Apr. 30, 1996 to Piantadosi et al. disclose nucleoside analogues conjugates to lipid moieties.
U.S. Pat. No. 5,525,727, issued Jun. 11, 1996 to Bodor disclose compositions for differential uptake and retention in brain tissue comprising a conjugate of a narcotic analgesic and agonists and antagonists thereof with a lipoidal form of dihydropyridine that forms a redox salt upon uptake across the blood-brain barrier that prevents partitioning back to the systemic circulation thereafter.
U.S. Pat. No. 5,543,389, issued Aug. 6, 1996 to Yatvin et al. discloses salves and ointments for delivering antiproliferative compounds to skin.
U.S. Pat. No. 5,554,728, issued Sep. 10, 1996 to Basava et al. discloses therapeutic peptides conjugated to lipid moieties.
U.S. Pat. No. 5,563,257, issued Oct. 8, 1998 to Zilch et al. disclose nucleoside analogues conjugates to ether lipid moieties.
U.S. Pat. No. 5,580,571, issued Dec. 3, 1996 to Hostetler et al. discloses nucleoside analogues conjugated to phospholipids.
U.S. Pat. No. 5,696,097, issued Dec. 9, 1997 to Matsuda et al. disclose nucleoside analogues conjugates to lipid moieties.
U.S. Pat. No. 5,744,461, issued Apr. 28, 1998 to Hostetler et al. disclose nucleoside analogues conjugated to phosphonoacetic acid lipid derivatives.
U.S. Pat. No. 5,744,592, issued Apr. 28, 1998 to Hostetler et al. discloses nucleoside analogues conjugated to phospholipids.
U.S. Pat. No. 5,756,116, issued May 26, 1998 to Hostetler et al. discloses nucleoside analogues.
U.S. Pat. No. 5,756,711, issued May 26, 1998 to Zilch et al. disclose nucleoside analogues conjugates to lipid moieties.
U.S. Pat. No. 5,827,819, issued Oct. 27, 1998 to Yatvin et al. disclose use of polar lipid conjugates to facilitate delivery of neurologic drugs to tissues of the central nervous system across the blood brain barrier.
U.S. Pat. No. 5,827,831, issued Oct. 27, 1998 to Hostetler et al. discloses phospholipid-drug conjugates having enhanced gastrointestinal bioavailability.
International Patent Application Publication Number WO85/02342, published 6 Jun. 1985 for Max-Planck Institute discloses a drug composition comprising a glycerolipid or derivative thereof.
International Patent Application Publication Number WO89/02733, published April 1989 to Vical discloses conjugates between antiviral nucleoside analogues and polar lipids, including phospholipids and ceramide.
International Patent Application Publication Number WO89/11299, published Nov. 30, 1989 for State of Oregon disclose a chemical conjugate of an antibody with a an enzyme which is delivered specifically to a brain lesion site for activating a separately-administered neurologically-active prodrug.
International Patent Application Publication Number WO91/04014, published 4 Apr. 1991 for Synergen, Inc. disclose methods for delivering therapeutic and diagnostic agents across the blood-brain barrier by encapsulating said drugs in liposomes targeted to brain tissue using transport-specific receptor ligands or antibodies.
International Patent Application Publication Number WO91/04745, published 18 Apr. 1991 for Athena Neurosciences, Inc. disclose transport across the blood-brain barrier using cell adhesion molecules and fragments thereof to increase the permeability of tight junctions in vascular endothelium.
International Patent Application Publication Number WO91/14438, published 3 Oct. 1991 for Columbia University disclose the use of a modified, chimeric monoclonal antibody for facilitating transport of substances across the blood-brain barrier.
International Patent Application Publication Number WO94/01131, published 20 Jan. 1994 for Eukarion, Inc. disclose lipidized proteins, including antibodies.
International Patent Application Publication Number WO94/03424, published 17 Feb. 1994 for Ishikura et al. disclose the use of amino acid derivatives as drug conjugates for facilitating transport across the blood-brain barrier.
International Patent Application Publication Number WO94/06450, published 31 Mar. 1994 for the University of Florida disclose conjugates of neurologically-active drugs with a dihydropyridine-type redox targeting moiety and comprising an amino acid linkage and an aliphatic residue.
International Patent Application Publication Number WO94/02178, published 3 Feb. 1994 for the U.S. Government, Department of Health and Human Services discloses antibody-targeted liposomes for delivery across the blood-brain barrier.
International Patent Application Publication Number WO95/07092, published 16 Mar. 1995 for the University of Medicine and Dentistry of New Jersey disclose the use of drug-growth factor conjugates for delivering drugs across the blood-brain barrier.
International Patent Application Publication Number WO96/00537, published 11 Jan. 1996 for Southern Research Institute disclose polymeric microspheres as injectable drug-delivery vehicles for delivering bioactive agents to sites within the central nervous system.
International Patent Application Publication Number WO96/04001, published 15 Feb. 1996 for Molecular/Structural Biotechnologies, Inc. disclose omega-3-fatty acid conjugates of neurologically-active drugs for brain tissue delivery.
International Patent Application Publication Number WO96/22303, published 25 Jul. 1996 for the Commonwealth Scientific and Industrial Research Organization disclose fatty acid and glycerolipid conjugates of neurologically-active drugs for brain tissue delivery.
International Patent Application Publication Number WO98/03204, published 29 Jan. 1998 for State of Oregon discloses salves and ointments for delivering antiproliferative compounds to skin.
International Patent Application Publication Number WO98/17325, published 30 Apr. 1998 for Oregon Health Sciences University discloses lipid conjugates with neurologically-active drugs.
An additional challenge in designing an appropriate drug delivery scheme is to include within the drug conjugate a functionality that could either accelerate or reduce the rate at which the drug is released upon arrival at the desired site. Such a functionality would be especially valuable if it allowed differential rates of drug release, or specific release only at the appropriate drug target site.
There remains a need in the art for an effective means for the specific delivery of biologically-active compounds, particularly antibacterial, antibiotic, antiviral, antimycotic, antiproliferative and antineoplastic drugs and agents, and also particularly neurotropic, psychotropic and anticonvulsant drugs and agents, and further particularly antineoplastic and anticancer drugs and agents, to physiologically restricted or protected sites. Advantageous embodiments of such delivery means are formulated to efficiently deliver the biologically-active compound to a physiologically-protected site, such as the brain or central nervous system, while minimizing hepatic and renal uptake of the agent or hematopoietic insult resulting therefrom.